The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). There are also N-terminally extended forms of at least NKA. At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, the receptors are classified as neurokinin-1 (NK1), neurokinin-2 (NK2) and neurokinin-3 (NK3) receptors, respectively. In the periphery, SP and NKA are localized in C-afferent sensory neurons, which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers. C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics. The effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation, increased mucus secretion and activation of mast cells. Thus, the tachykinins are implicated in the pathophysiology and airway hyperresponsiveness observed in asthmatics; and blockade of the action of released tachykinins may be useful in the treatment of asthma and related conditions.
This invention relates to naphthalenecarboxamide compounds N-substituted by an aminobutyl group, to pharmaceutical compositions containing such compounds, as well as to their uses and processes for their preparation. These compounds antagonize the pharmaco-logical actions of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin-1 (NK1) receptor. These compounds are useful whenever such antagonism is desired. Thus, such compounds are of value in the treatment of those diseases in which Substance P is implicated, for example, in the treatment of asthma, anxiety, depression, emesis and related conditions.
The N-substituted naphthalenecarboxamide compounds of the present invention show a high degree of NK1 receptor antagonist activity.
Accordingly the present invention provides the compounds of the formula (I):
R1R2Nxe2x80x94CH2CH2xe2x80x94CHAr1xe2x80x94CH2xe2x80x94NR3xe2x80x94COxe2x80x94R4 xe2x80x83xe2x80x83(I)
wherein:
R1 is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, C1-6alkanoyl, C1-6alkoxycarbonyl or arylcarbonyl; any of such groups being optionally substituted;
R2 is hydrogen or C1-6alkyl; or
R1 or R2 are joined to form an optionally substituted morpholino ring;
Ar1 is phenyl mono- or di-substituted by halo;
R3 is hydrogen or C1-6alkyl;
R4 is optionally substituted naphth-1-yl;
and pharmaceutically acceptable salts thereof.
When R1 is optionally substituted C2-6alkyl (for example ethyl or propyl), C2-6alkenyl (for example propenyl), C1-6alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) and C1-6alkanoyl (for example acetyl or propionyl), suitable substituents include halo for example chloro, bromo or fluoro; nitro; cyano; hydroxy; C1-6alkoxy for example methoxy or ethoxy; amino; C1-6alkylamino for example methylamino or ethylamino; di-C1-6alkylamino for example dimethylamino; trifluoromethyl; carboxy; carbamoyl (NH2COxe2x80x94); C1-6alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C1-6alkylcarbamoyl for example dimethyl-carbamoyl; C1-6alkanoyl for example acetyl; mercapto; C1-6alkylthio for example methylthio or ethylthio; C1-6alkylsulphinyl for example methylsulphinyl or ethylsulphinyl; C1-6alkylsulphonyl for example methylsulphonyl or ethylsulphonyl; sulphamoyl; C1-6alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; C3-8cycloalkyl for example cyclopropyl, cyclopentyl or cyclohexyl; cyclobutyl, aryl; or heteroaryl.
When R1 is substituted methyl, suitable substituents are C3-8cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; aryl; or heteroaryl.
When R1 is substituted aryl or arylcarbonyl (or when R1 and R2 together with the nitrogen atom to which they are joined form a morpholino ring) suitable substituents include those substituents mentioned hereinabove (for other values of R1), as well as C1-6alkyl for example methyl or ethyl, C2-6alkenyl for example allyl or vinyl; or C2-6alkynyl for example ethynyl.
xe2x80x9cArylxe2x80x9d in the terms xe2x80x9carylxe2x80x9d and xe2x80x9carylcarbonylxe2x80x9d means phenyl and naphthyl.
Preferably R1 is hydrogen, C1-6alkyl optionally substituted by phenyl, C2-6alkenyl, phenyl or benzoyl.
In particular R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, propen-2-yl, phenyl or benzoyl.
Preferably R2 is hydrogen or methyl.
In a particularly preferred aspect R1 is methyl or ethyl and R2 is hydrogen or methyl, for example R1R2Nxe2x80x94is methylamino.
In another preferred aspect R1 and R2 together with the nitrogen atom to which they are attached form a morpholino ring.
Favourably Ar1 is phenyl di-substituted by chloro, for example Ar1 is 3,4-dichlorophenyl.
R3 is hydrogen or C1-6alkyl for example methyl, ethyl or n-propyl. Preferably R3 is methyl.
R4 is optionally substituted naphth-1-yl. Suitable substituents, which are optional, for the naphth-1-yl group include hydroxy; cyano; nitro; trifluoromethoxy; trifluoromethyl; C1-6alkylsulfonyl for example methylsulphonyl; halo for example chloro, bromo, fluoro or iodo; C1-6alkoxy for example methoxy, ethoxy or propoxy; methylenedioxy (xe2x80x94OCH2Oxe2x80x94), C1-6alkyl for example methyl or ethyl; C2-6alkenyl for example ethenyl, prop-1-enyl or prop-2-enyl; C2-6alkynyl for example ethynyl; carboxy, C1-6alkoxy-carbonyl for example methoxycarbonyl; carbamoyl; C1-6alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C1-6alkylcarbamoyl for example di-methylcarbamoyl; C1-6alkanoyl for example acetyl or propionyl; C1-6alkanoylamino for example acetylamino or propionylamino; aminosulfonyl; and C1-6alkyl for example methyl substituted by any of the hereinabove substituents.
Favourably the naphth-1-yl group is unsubstituted or is substituted by up to three substituents. Preferred substituents for the naphth-1-yl group include cyano; nitro; C1-6alkylsulfonyl for example methylsulphonyl; halo for example chloro, bromo, fluoro or iodo; C1-6alkoxy for example methoxy, ethoxy, n-propoxy or isopropoxy; methylenedioxy (xe2x80x94OCH2 Oxe2x80x94); C1-6alkyl for example methyl or ethyl; C2-6alkenyl for example prop-2-enyl; C2-6alkynyl for example ethynyl; carboxy, carbamoyl; C1-6alkyl-carbamoyl for example methylcarbamoyl; di-C1-6alkylcarbamoyl for example di-methylcarbamoyl; C1-6alkanoyl for example acetyl; C1-6alkanoylamino for example acetylamino; aminosulfonyl; and cyanoC1-6alkyl for example cyanomethyl.
More preferred substitutents for the naphth-1-yl group are cyano, methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro, cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl, dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyl and acetylamino.
In particular the naphth-1-yl group may be substituted by up to two substituents selected from cyano, methoxy, ethyl, fluoro and nitro. A particularly preferred substitution pattern for the naphth-1-yl group is 3-cyano. A further particularly preferred substitution pattern is 3-cyano, 2-methoxy. Another particularly preferred substitution pattern is 2,3-dimethoxy. Another particularly preferred substitution pattern is 3-cyano, 2-ethyl.
The compounds of the present invention possess a chiral centre, at xe2x80x94CHAr1xe2x80x94 and possibly in the optional substituents. The present invention covers all isomers, diastereoisomers and mixtures thereof that antagonise NK1 receptors.
The preferred configuration at xe2x80x94CHAr1xe2x80x94 is shown in formula (Ia) hereinbelow: 
Thus a preferred class of compounds of the present invention is that of the formula (Ia) wherein R1 is hydrogen, methyl or ethyl; R2 is hydrogen or methyl; R3 is methyl; Ar1 is 3,4-dichlorophenyl; and R4 is naphth-1-yl optionally substituted by up to two substituents selected from cyano, methoxy, ethyl, fluoro and nitro.
Particular compounds of the invention are those of the Examples.
Pharmaceutically acceptable salts of the compounds of the formula (I) include those made with inorganic or organic acids which afford a physiologically acceptable anion, such as with, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric, malonic, fumaric, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicyclic and quinic acids.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in-standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. For example a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I or a pharmaceutically acceptable salt thereof may be used.
Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in a method of therapeutic treatment of the human or animal body.
In yet a further aspect the present invention provides a method of treating a disease condition wherein antagonism of the NK1 receptor is beneficial which comprises administering to a warm-blooded animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein antagonism of the NK, receptor is beneficial.
The compounds of the formula (I) and their pharmaceutically acceptable salts may be made by processes as described and exemplified herein and by processes similar thereto and by processes known in the chemical art. If not commercially available, starting materials for these processes may be made by procedures which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.
In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof which process comprises:
a) reacting a compound of the formula (Ill):
OHCxe2x80x94CH2xe2x80x94CHAr1xe2x80x94CH2xe2x80x94NR3xe2x80x94COR4 xe2x80x83xe2x80x83(III)
wherein Ar1, R3 and R4 are as hereinbefore defined with a compound of the formula R1 R2NH; or
b) reacting a compound of the formula (IV):
R1R2Nxe2x80x94CH2xe2x80x94CH2xe2x80x94CHAr1xe2x80x94CH2xe2x80x94NHR3 xe2x80x83xe2x80x83(IV)
wherein R, R2, R3 and Ar1 are as hereinbefore defined with a compound of the formula Lxe2x80x94COxe2x80x94R4 wherein L is a leaving group;
xe2x80x83wherein any functional group is protected, if necessary, and
i) removing any protecting group;
ii) optionally converting a compound of the formula (I) into another compound of the formula (D;
iii) optionally forming a pharmaceutically acceptable salt.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced and removed by conventional methods; see for example Protecting Groups in Organic Chemistry; Theodora W. Greene. Methods of removal are chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
It will also be appreciated that certain of the various optional substituents in the compounds of the formula (I) may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes described hereinabove. The reagents and reaction conditions for such procedures are well known in the chemical art.
Pharmaceutically acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the NK1 antagonist properties by the standard tests known in the art and those described hereinafter.
The compounds of the formulae (III) and R1R2NH are reacted under conditions of reductive amination. The reaction is typically performed at a non-extreme temperature, for example 0-100xc2x0 C., more suitably at ambient temperature, in a substantially inert solvent for example dichloromethane or methanol. Typical reducing agents include borohydrides such as sodium cyanoborohydride. The compounds of the formula R1R2NH are known or may be prepared in conventional manner. The compounds of the formula (III) may be prepared from the corresponding alcohol, which itself may be prepared by N-acylation of the corresponding substituted hydroxybutylamine.
The compounds of the formula (IV) and LCOR4 are reacted under conventional acylation conditions wherein LCOR4 is an acid or activated acid derivative such as an acid chloride. The compounds of the formula (IV) may be prepared by reacting a compound of the formula (V):
OHCxe2x80x94CH2xe2x80x94CHAr1 xe2x80x94CH2NHR3 xe2x80x83xe2x80x83(V)
wherein Ar1 and R3 are as hereinbefore defined, with R1R2NH under reductive amination conditions, with functional groups being protected as necessary. For example, when it is desired to prepare a compound of the formula (IV) when R3 is hydrogen, the xe2x80x94NHR3 function of the compound of the formula (V) may be protected as a phthalimido group, removal conventionally such as by hydrazinolysis. The compounds of the formula (V) are known or may be prepared in conventional manner for example from the corresponding substituted hydroxybutylamine.
The compounds of the formula (I) may be converted to other compounds of the formula (I), for example a compound of the formula (I) wherein R1 is hydrogen may be acylated in conventional manner to form the corresponding compound wherein R1 is arylcarbonyl or alkanoylcarbonyl.
The following biological test methods, data and Examples serve to illustrate and further describe the invention.
The utility of a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a xe2x80x9cCompoundxe2x80x9d) may be demonstrated by standard tests and clinical studies, including those disclosed in the publications described below.
SP Receptor Binding Assay (Test A)
The ability of a Compound of the invention to antagonize the binding of SP at the NK1 receptor may be demonstrated using an assay using the human NK1 receptor expressed in Mouse Erythroleukemia (MEL) cells. The human NK1 receptor was isolated and characterized as described in: B. Hopkins, et al. xe2x80x9cIsolation and characterization of the human lung NK1 receptor cDNAxe2x80x9d Biochem. Biophys. Res. Comm., 1991, 180, 1110-1117; and the NK1 receptor was expressed in Mouse Erythroleukemia (MEL) cells using a procedure similar to that described in Aharony, D., et al. xe2x80x9cIsolation and Pharmacological Characterization of a Hamster Neurokinin A Receptor cDNAxe2x80x9d Molecular Pharmacology, 1994, 45, 9-19. Rabbit Pulmonary Artery: NK1 in vitro Functional Assay (Test C)
The ability of a Compound of the invention to antagonize the action of the agonist Ac-[Arg6, Sar9, Met(O2)11] Substance P (6-11), ASMSP, in a pulmonary tissue may be demonstrated according to published methods; J. Pharmacol. Exp. Ther. 1993, 267, 1168; Buckner C K, Liberati N, Dea D, Lengel D, Stinson-Fisher C, Campbell J, Miller S, Shenvi A, Krell R D.
Male New Zealand white rabbits are euthanized via i.v. injection into an ear vein with 60 mg/kg Nembutal (50 mg/ml). Preceding the Nembutal into the vein is Heparin (1000 units/ml) at 0.0025 ml/kg for anticoagulant purposes. The chest cavity is opened from the top of the rib cage to the sternum and the heart, lungs and part of the trachea are removed. The pulmonary arteries are isolated from the rest of the tissues and cut in half to serve as pairs.
The segments are suspended between stainless steel stirrups, so as not to remove any of the endothelium, and placed in water-jacketed (37.0xc2x0 C.) tissue baths containing physiological salt solution of the following composition (mM): NaCl, 118.0; KCl, 4.7; CaCl2, 1.8; MgCl2, 0.54; NaH2PO4, 1.0; NaHCO3, 25.0; glucose, 11.0; indomethacin, 0.005 (to inihibit cyclooxygenase); and dl-Propranolol, 0.001 (to block xcex2 receptors); gassed continuously with 95% O2-5% CO2. Responses are measured on a Grass polygraph via Grass FT-03 transducers and the electrical signals (data) acquired using a Mi2 software/hardware system for subsequent conversion to measures of relaxation.
Initial tension placed on each tissue is 2 grams, which is maintained throughout the 1.0 hour equilibration period. Tissues are washed with the physiological salt solution at 15 minute intervals. At the 30 and 45 minute wash the following treatments are added: 1xc3x9710xe2x88x926M Thiorphan (to block E.C.3.4.24.11), 3xc3x9710xe2x88x928M (S)xe2x80x94N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide (to block NK2 receptors), and the given concentration of the Compound being tested. At the end of the 1.0 hour equilibration, 1xc3x9710xe2x88x926M L-Phenylephrine hydrochloride is added for 1.0 hour. At the end of the 1.0 hour, a dose relaxation curve to ASMSP is done. Each tissue is treated as a individual and is considered finished when it fails to relax further for 2 consecutive doses. When this section of the protocol is complete, 1xc3x9710xe2x88x923M Papaverine is added for maximum relaxation.
For non-competitive antagonists, the percent inhibition of relaxation is determined at a given concentration of the antagonist. Percent inhibition is determined when a tested Compound produces a statistically significant (p less than 0.05) reduction of the total relaxation which is calculated using the total relaxation as a percent of the control value. Potencies of competitive Compounds are determined by calculating the apparent dissociation constants (KB) for each concentration tested using the standard equation:
KB=[antagonist]/(dose ratioxe2x88x921)
where dose ratio=antilog[(agonistxe2x88x92log molar EC50 without Compound)xe2x88x92(xe2x88x92log molar EC50 with Compound)]. The KB values may be converted to the negative logarithms and expressed as xe2x88x92log molar KB (i.e. pKB). For this evaluation, complete concentration-response curves for agonist obtained in the absence and presence of the Compound tested using paired pulmonary artery rings. The potency of the agonist is determined at 50% of its own maximum relaxation in each curve. The EC50 values are converted to negative logarithms and expressed as xe2x88x92log molar EC50.
NK1 in vivo Functional Assay (Test E)
The activity of a compound as an antagonist of NK1 receptors also may be demonstrated in vivo in laboratory animals as described in: Buckner et al. xe2x80x9cDifferential Blockade by Tachykinin NK1 and NK2 Receptor Antagonists of Bronchoconstriction Induced by Direct-Acting Agonists and the Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotonin in the Anesthetized Guinea Pig.xe2x80x9d J. Pharm. Exp. Ther.,1993, Vol 267(3), pp1168-1175.
Results of testing of representative compounds of the present invention by the above methods are presented in the Table I:
Clinical Studies
Clinical studies to demonstrate the efficacy of a Compound of the invention may be carried out using standard methods.
The Tests provide evidence of general antagonism of SP. SP has been implicated in the pathology of numerous diseases including: rheumatoid arthritis, Alzheimer""s disease, cancer, schizophrenia, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, gastric asthma, gastroesphageal reflux, anxiety, emesis, Huntington""s Disease, psychoses including depression, hypertension, migraine and urticaria.
Accordingly, one feature of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a disease in a human or other mammal in need thereof in which SP is implicated and antagonism of its action is desired.
There is a possible role for Substance P antagonists in the treatment of depression. Accordingly another feature of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of depression in a human or other mammal in need thereof.
Because of the range of effects attributable to the actions of SP, compounds which are capable of blocking their actions may also be useful as tools for further evaluating the biological actions of other neurotransmitters in the Tachykinin family. As a result, another feature of the invention is provided by the use of a compound of Formula I or a salt thereof as a pharmacological standard for the development and standardization of new disease models or assays for use in developing new therapeutic agents for treating diseases in which SP are implicated or for assays for their diagnosis. The invention is illustrated by the following non-limiting examples, in which, where applicable and unless stated otherwise:
(i) operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25xc2x0 C.;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bath temperature of up to 60xc2x0 C.;
(iii) melting points are uncorrected;
(iv) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra;
(v) Mass spectra (MS) were run using an automated system with atmospheric pressure chemical ionization (APCI). Generally, only spectra where parent masses are observed are reported.
Abbreviations: CO, carbon monoxide; DCM, methylene chloride; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; Et2O, diethyl ether; EtOAc, ethyl acetate; h, hour(s); min, minutes; NMR, nuclear magnetic resonance; psi, pounds per square inch; THF, tetrahydrofuran.
Standard acylation refers to the typical procedure in which an acid chloride (1-1.2 equivalents) is added to a stirred solution of an amine (1-1.2 equivalents) and triethylamine (2 equivalents) in DCM. After 1-16 h the reaction is optionally concentrated, dissolved in DCM, and washed with saturated sodium bicarbonate and then purified by chromatography.
Standard reductive amination refers to the typical procedure in which a solution of an amine (1-1.2 equivalents), an aldehyde (1-1.2 equivalents) and acetic acid (2 equivalents) are stirred in methanol for 5 to 60 minutes before adding NaBH3CN (1.7 equivalents). After 1-16 h the reaction is optionally concentrated, dissolved in DCM, and washed with saturated sodium bicarbonate and then purified by chromatography.
Final compounds were converted to the citrate salt. The free base was combined with citric acid (1.0 equivalents) in methanol, concentrated under reduced pressure and dried under vacuum (25-50xc2x0 C.).